Understanding the genetic and molecular determinants of the neuroendocrine control of reproduction has been an important but elusive goal. Idiopathic hypogonadotropic hypogonadism (IHH) is a human disorder in which selective failure of the neuroendocrine components of sexual maturation occurs in the face of low levels of gonadotropins without any demonstrable anatomic cause. The considerable genetic and phenotypic heterogeneity of this condition suggests it is a rich source of unique information, not only about the neuroendocrine control of reproduction, but also about the development of several other organs. Thus, patients with IHH can be viewed as 'experiments of nature/ in which a series of mutations in genes both specific for the human and key to reproduction can be discovered. Utilizing clinical investigation and phenotyping, biochemical profiling, classical genetic studies, and new genomic tools, this proposal plans to address this issue using several unique resources. A broad spectrum of carefully profiled patients with these disorders has been assembled by the PI over the past 25 years and an evolving database of their phenotypic and genotypic features as well as a growing repository of their serum and DNA samples has been established. In our 1st aim, the 3 genes already known to cause this condition in a minority of IHH cases (KAL, DAX, and GnRH/rec) will be screened in this population. Subsequently, using iterative phenotyping, their full biologic spectrum will be defined in the 2nd aim. High throughput screening technologies will then be used to examine a wide spectrum of new candidate genes in this population and their phenotypes similarly identified in the 3rd aim. Finally, where appropriate, linkage analysis and genome mismatch scanning (GMS) will be employed in IHH families with known autosomal recessive inheritance. Together, this combination of resources and approaches should permit a unique opportunity to gain biologic insights into the genetic control of both GnRH and gonadotropin secretion in the human.